rs1554058577

Variant names:

• chr5-13810077-AGTCGAAGGCGGT-A
• rs1554058577
• NM_001369.3:c.7579_7590delACCGCCTTCGAC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM4 PP3 PP5_Moderate

The NM_001369.3(DNAH5):​c.7579_7590delACCGCCTTCGAC​(p.Thr2527_Asp2530del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,400,398 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T2527T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DNAH5 NM_001369.3 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.05
• Publications: 0 publications found

Genes affected

DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [provided by RefSeq, Oct 2009]

DNAH5 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001369.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 5-13810077-AGTCGAAGGCGGT-A is Pathogenic according to our data. Variant chr5-13810077-AGTCGAAGGCGGT-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 454804.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	NM_001369.3	MANE Select	c.7579_7590delACCGCCTTCGAC	p.Thr2527_Asp2530del	conservative_inframe_deletion	Exon 45 of 79	NP_001360.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.7579_7590delACCGCCTTCGAC	p.Thr2527_Asp2530del	conservative_inframe_deletion	Exon 45 of 79	ENSP00000265104.4
	DNAH5	ENST00000681290.1		c.7534_7545delACCGCCTTCGAC	p.Thr2512_Asp2515del	conservative_inframe_deletion	Exon 45 of 79	ENSP00000505288.1
	DNAH5	ENST00000512443.1	TSL:3	n.435_446delACCGCCTTCGAC		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1400398 Hom.: 0 AF XY: 0.00000145 AC XY: 1 AN XY: 691086

African (AFR) AF: 0.00 AC: 0 AN: 31726

American (AMR) AF: 0.00 AC: 0 AN: 36350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

East Asian (EAS) AF: 0.0000277 AC: 1 AN: 36048

South Asian (SAS) AF: 0.00 AC: 0 AN: 79370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080462

Other (OTH) AF: 0.00 AC: 0 AN: 57900

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Primary ciliary dyskinesia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0
Mutation Taster		=7/193	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554058577; hg19: chr5-13810186;